Metabolism and pharmacokinetics of 1-(2′-hydroxyethyl)- and 1-(3′-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-ones in the rat

Summary

The urinary recovery (p.o.) and pharmacokinetics (i.v. and p.o.) of two compounds from the 1-hydroxyalkyl-3-hydroxypyridin-4-one series. 1-(2′-hydroxyethyl)-2-ethyl-3-hydroxypyridin-4-one (CP102) and 1-(3′-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-one (CP106) were studied in the rat. The pharmacokinetics of the 1-carboxyethyl metabolite (CP110) of CP106 was also studied (i.v.). CP102 was not metabolised to any considerable extent with 68.4±12.2% of the administered dose recovered unchanged in rat urine. In contrast. CP106 undergoes extensive phase I metabolism to form the 1-carboxyalkyl metabolite which accounted for 56.4±11% of the administered dose with 22.0±1.0% as unchanged drug. Intravenous and oral pharmacokinetics of CP102 and CP106 were studied in the rat at 450 μmoles/kg. The AUCs of CP102 and CP106 after bolus i.v. infusion were 458±38 and 171±20 μmoles/l.h. The AUC values after bolus oral administration were 318±46 and 77±18 μmoles/l.h, respectively, with corresponding bioavailabilities (F) of 0.69 and 0.45. The C_max of CP102 and CP106 were 142±25 and 70±15 μmoles/l with T_max values of 0.75±0.15 and 0.50±0.10 h, respectively. The CL, MRT and Vd_ss of CP102 was 1.00±0.09 l/kg/h, 0.92±0.04 h and 0.91±0.05 l/kg, respectively. The corresponding pharmacokinetic parameters for CP106 were 2.64±0.20 l/kg/h, 0.42±0.12 h and 1.12±0.26 l/kg, respectively. Renal clearance (CL_R) of CP102 and CP106 were 1.00±0.18 l/kg and 1.27±0.31 l/kg respectively. The pharmacokinetics of CP110, which was conducted by the i.v. route only at a dose of 450 μmoles/kg, had an AUC of 289±46 μmoles/l.h, CL of 1.56±0.29 l/kg/h, MRT of 0.25±0.09 h and Vd_ss of 0.40±0.13 l/kg, respectively.